The mGlu5 subtype of metabotropic glutamate (mGlu) receptor has emerged as an exciting potential target for novel therapeutic agents for treatment of schizophrenia and other disorders that include impaired cognitive function. We have developed highly selective positive allosteric modulators (PAMs) for mGlu5 that have robust antipsychotic-like effects and improve multiple domains of cognitive function in rodent models. In addition to providing a promising new potential therapeutic strategy for treatment of schizophrenia and other brain disorders, these novel agents are providing exciting new insights into the functional roles of mGlu5 in brain circuits that are relevant for their cognition-enhancin and other behavioral effects. Most recently, we developed novel mGlu5 PAMs that selectively potentiate mGlu5 coupling to specific signaling pathways and physiological responses. The stimulus bias provided by these exciting new tools provides an unprecedented opportunity to determine the functional effects of selectively potentiating specific physiological responses to mGlu5 activation. One of the most exciting properties of mGlu5 PAMs is that these compounds can enhance different forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), while maintaining a strict dependence of each on specific patterns of afferent activity. The ability of mGlu5 PAMs to potentiate hippocampal LTP has been postulated to be mediated by enhancing mGlu5-induced potentiation of currents through the NMDA glutamate receptor subtype (NMDAR). However, recent studies suggest that potentiation of NMDAR function may also lead to severe adverse effects of mGlu5 PAMs. We have now identified novel mGlu5 PAMs that do not potentiate mGlu5 modulation of NMDAR currents but enhance hippocampal LTP. We propose a series of studies in which we will use these novel molecular probes along with genetic mouse models to test the hypothesis that mGlu5 PAMs do not enhance LTP by potentiating mGlu5 modulation of NMDAR currents, but potentiate LTP and specific aspects of hippocampal-dependent cognitive function by enhancing endocannabinoid release and subsequent disinhibition of CA1 pyramidal cells. We also provide exciting new preliminary data suggesting that mGlu5 activation is required for a form of NMDAR-independent LTD in the prefrontal cortex (PFC) that could contribute to some aspects of in vivo efficacy of mGlu5 PAMs. We will now perform studies to test the hypothesis that mGlu5 PAMs enhance mLTD in the PFC and enhance specific forms of PFC-dependent cognitive function, and that this does not require direct effects on mGlu5 modulation of NMDAR currents. Finally, both PFC mLTD and hippocampal LTP are disrupted in rodent models of schizophrenia and these deficits in synaptic plasticity are accompanied by behavioral deficits in cognitive function. We will also test the hypothesis that mGlu5 PAMs can restore deficits in hippocampal LTP and PFC mLTD and behavioral deficits in a rodent model of schizophrenia.